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EC number: 206-992-3 | CAS number: 420-04-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1990
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 990
- Report date:
- 1990
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Version / remarks:
- (1981)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-4 (Reproduction and Fertility Effects)
- Version / remarks:
- (1982)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Cyanamide
- EC Number:
- 206-992-3
- EC Name:
- Cyanamide
- Cas Number:
- 420-04-2
- Molecular formula:
- CH2N2
- IUPAC Name:
- cyanamide
- Test material form:
- other: aqueous solution
- Details on test material:
- -Test susbtance: Aqueous hydrogen cyanamide
- Purity: 50 % (w/w)
- Appearance: Clear colourless liquid
- Lot/Batch number: 07/07/87
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- The rats were 7 week old.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- the dosing solutions were prepared weekly by dilution with distilled water and were stored under refrigeration. Approximately 1 hour prior to application the solutions were thawed and stirred during dosing. The application volume was 10 ml/kg bw.
- Details on mating procedure:
- One female was mated with one male overnight for a period of up to 3 weeks to produce the F1 litter. From the F1 pups 26 males and 26 females/dose group were selected as F1 parental generation to produce the F2 generation.
- Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- 14 weeks prior to mating, and dosing continued until termination.
- Frequency of treatment:
- Daily
- Details on study schedule:
- F0 males were dosed once daily for approximately 14 weeks prior to mating, and dosing continued until termination. F0 females were dosed once daily for approximately 14 weeks prior to mating and throughout the mating, pregnancy, lactation and post lactation periods. 1 female was mated with 1 male overnight for a period of up to 3 weeks to produce the F1 litter. From the F1 pups 26 males and 26 females/dose group were selected as F1 parental generation to produce the F2 generation following treatment with dose levels of 0, 1.25, 3.75 and 15.0 mg/kg bw/day for at least 14 weeks.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Remarks:
- (corresponding to 2.5 mg/kg bw/day active ingredient) for 12 weeks
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Remarks:
- (corresponding to 7.5 mg/kg bw/day active ingredient) for 12 weeks
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Remarks:
- (corresponding to 30.0 mg/kg bw/day active ingredient) for 12 weeks
- Dose / conc.:
- 2.5 mg/kg bw/day (nominal)
- Remarks:
- (corresponding to 1.25 mg/kg bw/day pure active ingredient) from week 12 onwards
- Dose / conc.:
- 7.5 mg/kg bw/day (nominal)
- Remarks:
- (corresponding to 3.75 mg/kg bw/day pure active ingredient) from week 12 onwards
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Remarks:
- (corresponding to 15.0 mg/kg bw/day pure active ingredient) from week 12 onwards
- No. of animals per sex per dose:
- 26 animals per sex per dose
- Control animals:
- yes, sham-exposed
- Details on study design:
- From the beginning of week 12 the doses were lowered due to severe impact on health expressed by loss in body weights of the F0 high dose animals.
- Positive control:
- No positive control
Examinations
- Parental animals: Observations and examinations:
- The examination of parental animals included monitoring for clinical symptoms/mortalities, food consumption, body weight development, mating and reproductive performances.
- Litter observations:
- All pups were examined macroscopically at necropsy (external and organ findings), stillborn pups and pups that died intercurrently were additionally examined for any skeletal findings.Litter size reduction in litters with more than 8 pups was performed on postnatal day 4.
- Postmortem examinations (parental animals):
- Pathological examination was performed by gross inspection as well as by histopathological examination with special attention to the organs of the reproductive system. Pups were sexed, weighed and monitored with respect to their viability and growth.
- Postmortem examinations (offspring):
- Culled pups were sacrificed by intraperitoneal injection of sodium pentobarbital and examined for visceral abnormalities.
- Statistics:
- A significant difference between the control and the treated groups was statistically examined by the Dunnett´s test (p < 0.05, p< 0.01).
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
Details on results (P0)
After reduction of the dose levels towards the end of pre-mating, the body weight gain improved and especially the males of all treatment groups gained weight above the respective control during the post-mating period.
Mating ability was unimpaired by treatment in the F0 (and the F1 generation). Most females mated during the first oestrus and the distribution of matings that occurred at second oestrus or later did not indicate a test substance-related effect. A low fertility and gestation index were obtained in the F0 animals at the high dose group.
Gross pathological and histopathological data from F0 (and F1 adults) did not reveal any significant treatment-related changes.
Effect levels (P0)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- for maternal and developmental parameters
- Effect level:
- 1.25 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: 1.25 mg/kg bw/day of the pure active ingredient cyanamide.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- for reproduction pararmeters
- Effect level:
- 3.75 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: 3.75 mg/kg bw/day of the pure active ingredient cyanamide.
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
Mating ability was unimpaired by treatment in the F0 and the F1 generation. Most females mated during the first oestrus and the distribution of matings that occurred at second oestrus or later did not indicate a test substance-related effect. Low fertility and gestation indices were obtained in the F1 (and F0).
No substance-induced morphological abnormalities were found in the offspring. Neonatal survival (day 0 - 4) of the F1 and the F2 pups, however, was significantly lower in all treated groups compared to the control group. The investigators do not consider this to be treatment-related because of considerable variability in the historical data base. However, the historical data have not been provided for comparison and the reviewer considers the concurrent control to be more representative for the actual study conditions than historical control ranges.
F1 neonates had reduced birth weights in the mid and high dose group. Although the finding in the intermediate dose could be related to the higher mean live litter size the comparison with the low dose indicates that a test substance effect on foetal growth was present. Weaning weights were also lower in the mid and high dose groups. For the F2 pups at the high dose level a slight effect on birth weight was observed and the weights attained at weaning were marginally lower than in the control.
Birth weights of the F1 and F2 pups were not affected. In the F1 pup growth during lactation was retarded in the mid and high dose groups compared to the control group but not during raise of the F2 pups.
No treatment-related morphological alterations were observed in the F1 and F2 pups during inspection for cervical, thoracic and abdominal visceral abnormalities in the culled, intermittent died or scheduled killed pups.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1.25 mg/kg bw/day
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 30 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to other toxic effects:
- not specified
- Dose response relationship:
- yes
Any other information on results incl. tables
Body weight gain data of F0/F1 parental animals:
Dose level (mg/kg bw/day) | 0 | 2.5 | 7.5 | 30 |
F0 males - pre-mating (week 0-12) | 271 | 249 | 224** | 108** |
F0 females |
|
|
|
|
- pre-mating (week 0-12) | 129 | 126 | 106** | 59** |
Dose level (mg/kg bw/day) | 0 | 1.25 | 3.75 | 15 |
F0 males - post-mating (week 12-24) | 68 | 92* | 106* | 99* |
F0 females |
|
|
|
|
- pregnancy (GD 0-20) | 130 | 143 | 139 | 111 |
- lactation (PND 0-21) | -1.4 | 0.6 | 3.0 | 25 |
F 1 males - pre-mating (week 0-12) | 461 | 446 | 441 | 391* |
F 1 males - postmating (week 12-27) | 111 | 101 | 87* | 36* |
F 1 females |
|
|
|
|
- pre-mating (week 0-12) | 221 | 232 | 222 | 202** |
- pregnancy (GD 0-20) | 119 | 129 | 126 | 94** |
- lactation | 1.4 | -7.5 | 6.6 | 27** |
* p < 0.05; ** P < 0.01 (Dunnett test) |
Fertility and litter data of F0/F1 generation animals:
Dose level (mg/kg bw/day) | 0 | 1.25 | 3.75 | 15 |
F0 generation |
|
|
|
|
Cohabitated pairs | 26 | 26 | 26 | 26 |
Mated females | 26 | 22 | 24 | 23 |
Pregnant females | 20 | 20 | 20 | 15* |
Female fertility index (%) | 77 | 91 | 83 | 65 |
Male fertility index (%) | 80 | 91 | 83 | 65 |
Gestation index (%) | 100 | 100 | 100 | 80 |
Mean duration of pregnancy (days) | 22.06 | 22.11 | 21.89 | 22.10 |
Total prenatal litter loss | 0 | 0 | 0 | 3 |
Live litters | 20 | 20 | 20 | 12 |
Pups delivered (mean) | 13.15 | 15.00 | 14.95 | 10.83 |
Live birth index (%) | 98 | 96 | 96 | 99 |
Viability index (alive PND 0-4) | 92 | 83** | 88** | 84** |
(HCD: 94.7%±5.6, Min.: 84% - Max.: 98%, supplied by breeder) | ||||
(HCD: % dead pups prior to culling: 2.76% ±2.76, Min.: 0.0% - Max.: 13.1% supplied by MARTA, 1996) | ||||
Weaning index (alive PND 4–21) | 92 | 85 | 87 | 88 |
(HCD: 95.2%±10.9, Min.: 73% - Max.: 100%, supplied by breeder) | ||||
(HCD: % dead pups post-culling - weaning: 0.71% ±1.28, Min.: 0.0% - Max.: 8.6% supplied by MARTA, 1996) | ||||
Male pup weight PND 0 (g) | 6.70 | 6.59 | 6.49 | 6.28 |
Female pup weight PND 0 (g) | 6.34 | 6.27 | 6.05 | 5.89 |
Male pup weight PND 21(g) | 50.48 | 47.13 | 43.20* | 42.62* |
Female pup weight PND 21 (g) | 49.04 | 47.03 | 40.43** | 42.26* |
F1 generation |
|
|
|
|
Cohabitated pairs | 26 | 26 | 26 | 26 |
Mated females | 25 | 24 | 26 | 23 |
Pregnant females | 24 | 21 | 23 | 19 |
Female fertility index (%) | 96 | 88 | 88 | 83 |
Male fertility index (%) | 96 | 88 | 88 | 83 |
Gestation index (%) | 96 | 95 | 91 | 89 |
Mean duration of pregnancy (days) | 21.8 | 22.0 | 21.9 | 22.0 |
Total prenatal litter loss | 0 | 0 | 2 | 2 |
Live litters | 23 | 20 | 21 | 17 |
Pups delivered (mean) | 12.87 | 13.45 | 15.05* | 12.29 |
Live birth index (%) | 98 | 98 | 98 | 95 |
Viability index (alive PND 0-4) | 93 | 87* | 82** | 81** |
(HCD: 94.7%±5.6, Min.: 84% - Max.: 98%, supplied by breeder) | ||||
(HCD: % dead pups prior to culling: 2.76% ±2.76, Min.: 0.0% - Max.: 13.1% supplied by MARTA, 1996) | ||||
Weaning index (alive PND 4–21) | 87 | 81 | 87 | 97* |
(HCD: 95.2%±10.9, Min.: 73% - Max.: 100%, supplied by breeder) | ||||
(HCD: % dead pups postculling - weaning: 0.71% ±1.28, Min.: 0.0% - Max.: 8.6% supplied by MARTA, 1996) | ||||
Male pup weight PND 0 (g) | 6.42 | 6.57 | 6.58 | 6.20 |
Female pup weight PND 0 (g) | 6.02 | 6.14 | 6.24 | 5.83 |
Male pup weight PND 21 (g) | 44.77 | 43.11 | 43.78 | 42.65 |
Female pup weight PND 21 (g) | 43.22 | 42.68 | 41.13 | 39.99 |
It should be taken in account that due to the change of dose levels just before mating of the F0 animals, the apparent effects on fertility and neonatal growth and survival both in the highest dose group were attributed to treatment but cannot be attributed to a specific dose level. The general health of these animals was influenced and not comparable to that of the control animals at the time of mating and the reproductive effects occurred in the presence of a clear maternal effect.
Applicant's summary and conclusion
- Conclusions:
- The following findings were obtained in study: Clinical findings, reduced body weight and food consumption in parental animals of mid and high dose (F0 and F1 generation).
Reduced fertility at high dose. Retarded body weight gain (F1 pups) and reduced survival (F2 pups) in mid and high dose group. No morphological alterations were seen.
Thus, NOAEL of 1.25 mg/kg bw/day pure active ingredient cyanamide was determined for maternal and developmental parameters and NOAEL of 3.75 mg/kg bw/day pure active ingredient was determined for reproduction parameters - Executive summary:
The continuous application of aqueous hydrogen cyanamide to Sprague-Dawley rats over two generations at dose levels of 0, 2.5, 7.5 and 30 mg/kg bw/day pure active ingredient during the first 12 weeks of treatment followed by 0, 1.25, 3.75 and 15 mg/kg bw/day of pure active ingredient orally by gavage affected reproductive performance and fertility of the F0 or F1 parental animals only in form of reduced fertility indices in F0 and F1 parental animals at the top dose group of 30/15 mg/kg bw/day active ingredient. All other observable differences between both of these groups and the concurrent controls were regarded to be incidental in nature and not of toxicological or biological concern.
Signs of general, systemic toxicity in both parental generations (F0 and F1) were confined to the rats of the mid and high dose levels. Toxicity was characterized by effects on food consumption and body weights and body weight gain during premating within the first 12 weeks. After reduction of the dose levels prior to mating of the F0 parental animals, the health status improved continuously. However, an impairment of body weight gain was also noted for the F1 parental males at the mid and high dose level (i.e. e. 3.75 and 15 mg/kg bw/day active ingredient) especially in the post-mating period and for the high dose F1 males during pre- and post-mating as well as for the high dose F1 females during premating and gestation. Concerning pathology, none of the recorded gross lesions or microscopic findings in the F0 and F1 generation parental animals was interpreted to represent an adverse treatment related effect.
Substance induced signs of developmental toxicity were observed in the progeny of the F0 parental generation in form of retarded body weight gain and in the F2 pups in form of reduced survival during early postnatal live resulting in decreased viability indices in the mid and high dose groups. In none of the F1 or F2 pups substance-induced morphological alterations were noted by external and visceral inspection.
Thus, under the conditions of this study the NOAEL (no observed adverse effect level) for reproductive performance and fertility is 3.75 mg/kg bw/day pure active ingredient due to the reduced fertility indices in both generations. The NOAEL for parental and developmental toxicity is considered to be 1.25 mg/kg bw/day pure active ingredient.
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